Drosophila
            carboxypeptidase D (
            SILVER
            ) is a key enzyme in neuropeptide processing required to maintain locomotor activity levels and survival rate

AbstractNeuropeptides are processed from larger preproproteins by a dedicated set of enzymes. The molecular and biochemical mechanisms underlying preproprotein processing and the functional importance of processing enzymes are well characterised in mammals, but little studied outside this group. In contrast to mammals, Drosophila lacks a gene for carboxypeptidase E (CPE), a key enzyme for mammalian peptide processing.By combining peptidomics and neurogenetics, we addressed the role of Drosophila carboxypeptidase D (dCPD) in global neuropeptide processing and selected peptide-regulated behaviours. We found that a deficiency in dCPD results in C-terminally extended peptides across the peptidome, suggesting that dCPD took over CPE function in the fruit fly. dCPD is widely expressed throughout the nervous system, including peptidergic neurons in the mushroom body and neuroendocrine cells expressing adipokinetic hormone. Conditional hypomorphic mutation in the dCPD-encoding gene silver in the larva causes lethality, and leads to deficits in adult starvation-induced hyperactivity and appetitive gustatory preference, as well as to reduced survival rate and activity levels. A phylogenomic analysis suggests that loss of CPE is not a common insect feature, but specifically occured in Hymenoptera and Diptera. Our results show that dCPD is a key enzyme for neuropeptide processing in Drosophila, and is required for proper peptide-regulated behaviour. dCPD thus appears as a suitable target to genetically shut down total neuropeptide production in peptidergic neurons. Our results raise the question why Drosophila and other Diptera and Hymenoptera –unlike other insects-have obviously lost the gene for CPE but kept a gene encoding CPD.

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Search and evaluation of pharmacodynamic and pharmacokinetic parameters of selective blocker of TRPA 1 ion channels from the group of substituted pyrazinopyrimidinones

Research Results in Pharmacology ◽

10.3897/rrpharmacology.4.30303 ◽

2018 ◽

Vol 4 (3) ◽

pp. 49-62

Author(s):

Evgeniya А. Beskhmelnitsyna ◽

Dmitriy V. Kravchenko ◽

Lev N. Sernov ◽

Irina N. Dolzhikova ◽

Tatyana V. Avtina ◽

...

Keyword(s):

Locomotor Activity ◽

Laboratory Animals ◽

Absolute Bioavailability ◽

Organ Distribution ◽

Pharmacokinetic Parameters ◽

In Vitro Tests ◽

Activity Levels ◽

General Locomotor Activity ◽

Anti Inflammatory

Introduction. Doctors of almost all specialties have to deal with the problem of pain and its relief. According to the literature, almost 30 million people daily take analgesics from the group of non-opioid analgesics, but in more than half of them 4-6 hours after taking the medication, the severity of pain is unchanged. Objective. to search for the most active molecules potential selective inhibitors of the TRPA1 ion channel with further investigation of their pharmacodynamic effects, toxicological safety, pharmacokinetic parameters and organ distribution, as well as to assess their impact on the psychoemotional state, general locomotor activity levels and anxiety in laboratory animals. Materials and methods. According to the results of in vitro tests, the most active molecule under code ZC02-0012 was selected from the pool of candidates. Further its analgesic activity was evaluated using an acetic acid-induced writhing test and a hot plate test; its anti-inflammatory activity was studied in the acute exudative paw edema model; in the open field and elevated plus-maze tests the influence of ZC02-0012 on the general locomotor activity levels and the anxiety of the laboratory animals was studied. The pharmacokinetic parameters and organ distribution of the substance ZC02-0012 were studied using a liquid chromatograph with an operating pressure range of 0-60 mPa (Thermo Scientific Dionex UltiMate 3000). Results and discussion. According to the results of in vitro tests, it was found that IC50 of the TRPA1 selective inhibitor under laboratory code ZC02-0012 was 91.3 nmol. The preclinical studies showed that ZC02-0012 possessed pronounced analgesic and anti-inflammatory activities and absence of the influence on the behavior and anxiety of the laboratory animals. Absolute bioavailability of ZC02-0012 in rabbits was 47%, while ZC02-0012 was intensely distributed into organs and tissues with a high level of blood circulation. The highest content of ZC02-0012 is typical of liver, kidneys and lungs, the lowest – for muscle tissue. Most of the substance is undergone rapid biotransformation and excreted as metabolites.

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Ethanol-induced stimulation and depression on measures of locomotor activity: Effects of basal activity levels in rats

Alcohol ◽

10.1016/0741-8329(93)90078-3 ◽

1993 ◽

Vol 10 (6) ◽

pp. 537-540 ◽

Cited By ~ 19

Author(s):

Timothy O. Moore ◽

Harry L. June ◽

Michael J. Lewis

Keyword(s):

Locomotor Activity ◽

Activity Levels ◽

Basal Activity

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